Steroids and related hormones play an important role in regulating development, differentiation and homeostasis. The hormones exert their regulatory effects by binding to a superfamily of intracellular receptors, which are direct modulators of gene transcription. Mutational analyses of hormone receptors have identified functional domains responsible for transcriptional activation, nuclear localization, DNA binding, and hormone binding.
Hormone receptors can act to both activate transcription, and to repress expression of a variety of genes. It has been postulated that such repression is mediated by binding of the hormone receptor to DNA regulatory sequences, termed negative hormone response elements, thereby displacing transcriptional activators.
It would be desirable to be able to control the degree to which hormones, either directly or indirectly, activate transactivation and/or the degree to which hormones, either directly or indirectly, repress the expression of certain genes, for such purposes as the treatment of disease states, the development of treating agents with reduced incidence of side effects, and so forth.
The AP-1 protein complex is a member of a class of nuclear proteins encoded by proto-oncogenes that have been implicated in diverse aspects of cell growth, differentiation, and development. The AP-1 binding site is recognized by c-Jun homodimers and c-Jun/c-Fos heterodimers. Binding of c-Fos to the AP-1 site is dependent on the formation of heterodimers with c-Jun. Homodimer and heterodimer formation is mediated through non-covalent interactions facilitated by a structure termed the leucine zipper. In addition to imparting positive regulatory effects on several pathways, the AP-1 complex has also been shown to confer negative regulation on several genes.
Up until now, the effect of a given protein on gene regulation has generally been thought to be the result of interaction between the protein and a regulatory element within the promoter region of the gene being regulated. Thus, compounds which exert an effect on more than one pathway are thought to recognize a responsive element which is common to more than one pathway. Consistent with this, Diamond et al., [in Science 249: 1266-1272 (1990)] describe studies employing a "composite" glucocorticoid response element (GRE), which binds selectively in vitro to both glucocorticoid receptor and c-Jun and c-Fos (components of the phorbol ester-activated AP-1 transcription factor). The authors then propose a general model for composite GRE action that requires DNA binding for interaction between receptor (i.e., glucocorticoid receptor) and non-receptor factors (i.e., c-Jun or c-Fos).
Based on the above-described understanding of the mechanism by which regulatory proteins exert their effects, it would not be possible to alter one regulatory effect of a given protein without also altering some other regulatory effects of that protein. Thus, for any beneficial effect achieved by administration of a hormone or hormone analog, there is a strong likelihood that an undesirable side effect will occur, i.e., promotion of undesired processes and/or inhibition of desired processes. Accordingly, there has been no motivation in the art to search for compounds which are capable of disrupting a known pathway without also undesirably impacting other regulatory pathways.